Diabetes – A 21st Century Epidemic Diagnosis and what is it A common disease An expensive disease A serious disease A treatable disease A preventable disease

Diagnosis and what is it Glucose Tolerance Categories FPG 126 mg/dL 100 mg/dL 7.0 mmol/L 5.7 mmol/L Impaired Fasting Glucose Normal 2-Hour PG on OGTT 200 mg/dL 140 mg/dL 11.1 mmol/L 7.8 Diabetes Mellitus Impaired Glucose Tolerance Slide 4 Glucose Tolerance Categories Either the fasting plasma glucose (FPG) test or the 2-hour plasma glucose (PG) determination during the oral glucose tolerance test (OGTT) may be used to determine glucose tolerance status. According to the most recent diagnostic criteria established by The Expert Committee on the Diagnosis and Class- ification of Diabetes Mellitus, an FPG value 126 mg/dL (7.0 mmol/L) or a 2-hour plasma glucose value 200 mg/dL (11.1 mmol/L) are the new cutoff points for the diagnosis of diabetes. The cutoff points for the intermediate stage of hyperglycemia denoted by the terms impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) have been adjusted to conform to the new diagnostic criteria for diabetes mellitus. IFG is now defined by FPG 110 mg/dL (6.1 mmol/L) and <126 mg/dL (<7.0 mmol/L), and IGT is defined by 2-hour PG measurements 140 mg/dL (7.8 mmol/L) and <200 mg/dL (<11.1 mmol/L). The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197. Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.

What is it ? Diabetes is a Vascular Disease Background Retinopathy % Affected 100 125 150 175 200 Fasting Plasma Glucose

Natural History of Type 2 Diabetes Post-meal glucose 350 250 100 300 200 150 IGT Diabetes Glucose (mg/dL) Fasting glucose -15 -10 -5 5 10 15 20 25 75 50 25 100 125 Relative Function (%) Insulin resistance ß-cell -15 -10 -5 5 10 15 20 25 Years of Diabetes Adapted from: International Diabetes Center (Minneapolis, Minnesota). 4

Etiologic Classification of Diabetes Mellitus Type 1 b-cell destruction with lack of insulin Type 2 Insulin resistance with insulin deficiency Other specific types Genetic defects in b-cell function, exocrine pancreas diseases, endo- crinopathies, drug- or chemical- induced, and other rare forms Gestational Insulin resistance with b-cell dysfunction Slide 3 Etiologic Classification of Diabetes Mellitus Diabetes mellitus is best described as a group of metabolic diseases character- ized by hyperglycemia. The hyperglycemia may be the result of defects in insulin secretion or insulin sensitivity, or both. Two major forms of diabetes are recognized in the most recent classification scheme, which was developed by The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, an international group, and has been adopted by both the American Diabetes Association and the World Health Organization. Type 1 diabetes includes almost all cases that are marked by destruction of the pancreatic islet -cells. Type 2 diabetes includes those cases that result from insulin resistance accompanied by a defect in insulin secretion. Other specific forms of diabetes, which affect far fewer patients than the two major forms, include genetic defects of -cell function, genetic defects in insulin sensitivity, diseases of the exocrine pancreas, endocrinopathies, drug- or chemical-induced infections, uncommon immune-mediated conditions, and other genetic conditions. Gestational diabetes mellitus is a fourth type in this new classification system. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197. Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183-1197.

Diabetes in the U.S. 23.6 million (10.7% ≥ 20 y.o) at a cost of $174 billion in 2007 57 million with prediabetes 6th disease specific cause of death. Leading cause of: Kidney failure. Adult blindness. Nontraumatic limb amputation. Cardiovascular disease. ADA. Diabetes Care 31:596-615, 2008 6

Diabetes is a Common Disease : Estimated Prevalence of Diabetes in the US: Adult Men and Women 30 Men Women 21.1 20.2 20 17.8 17.5 Percent of Population 12.9 12.4 10 6.8 6.1 Slide 7 Estimated Prevalence of Diabetes in the US: Adult Men and Woman The 1997 prevalence of diagnosed diabetes among adults aged 20 years or older was estimated using data collected in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. The most recent diagnostic criteria for diabetes (fasting plasma glucose [FPG] 126 mg/dL) was applied (see Slides 4 and 5). Prevalence rates rose with age, with a plateau after age 75 years. The highest prevalence rates (17.5% to 21.1%) were found in the 60- to 74- and 75+ -year age groups. Harris M, Flegal K, Cowie C, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. Diabetes Care. 1998;21:518-524. 1.6 1.7 20-39 40-49 50-59 60-74 75+ Age (y) Harris, et al. Diabetes Care. 1998;21:518-524, with permission.

Estimated Prevalence of Diabetes in the US: Breakdown by Ethnicity 10 9.3 Diagnosed 8.2 Undiagnosed 8 6 Percent of Population 4.8 4.5 4 3.6 2.5 Slide 9 Estimated Prevalence of Diabetes in the US: Breakdown by Ethnicity According to estimates developed using data from the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994, and applying the new diagnostic criteria for diabetes (see Slides 4 and 5), estimates for the prevalence of diabetes (diagnosed and undiagnosed) were developed for adults of different ethnicities. Diabetes (diagnosed and undiagnosed) is more prevalent among African Americans and Hispanic Americans than among non-Hispanic white Americans, and the proportion of undiagnosed cases is higher. Harris M, Flegal K, Cowie C, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. Diabetes Care. 1998;21:518-524. 2 Non-Hispanic African Hispanic White American American Data from Harris, et al. Diabetes Care. 1998;21:518-524.

Diabetes – An expensive disease Direct and indirect costs of diabetes estimated to be $174 Billion annually in the USA in 2007 Costs to most health systems is 2-3 fold greater annually for patients with diabetes

1997 Per Capita Health Care Costs: Persons With and Without Diabetes 25 23.5 Diabetes No diabetes 20 15 Annual Costs ($1000s) 12.2 10 Slide 10 1997 Per Capita Health Care Costs: Persons With and Without Diabetes National health care survey data from the National Center for Health Statistics were used to estimate per capita annual health care costs for persons with and without diabetes. On a per capita basis, persons with diabetes had significantly higher medical costs than did persons without this disease. Per capita inpatient costs were doubled for patients with diabetes compared to those without ($23,501 vs $12,220). Drug costs were approximately three times higher among persons with diabetes versus those without ($2,550 vs $1,457). American Diabetes Association. Economic consequences of diabetes mellitus in the U.S. in 1997. Diabetes Care. 1998;21:296-309. 5 2.5 1.5 0.7 0.4 0.7 0.4 0.7 0.2 Inpatient Outpatient ER Office Outpatient Services Visits Drugs Data from American Diabetes Association. Diabetes Care. 1998;21:296-309.

Diabetes – A serious but treatable disease Microvascular complications Blindness, renal failure and nerve dysfunction Macrovascular complications Atherosclerosis –MI, Stroke and amputations Hypertension - Stroke, CHF, CAD

The Arterial Tree in Diabetes Conduit Artery Resistance Precapillary Capillaries Arterioles Arterioles Atherosclerosis Hypertension Retinopathy Neuropathy Nephropathy

Intermittent claudication Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 10 9 Men Women 8 11 Risk ratio 6 30 19 4 38 9 6 20 3* 2 Total CVD CHD Cardiac failure Intermittent claudication Stroke Age-adjusted annual rate/1,000 P<0.001 for all values except *P<0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.

Women, Diabetes, and CHD Diabetic women are at high risk for CHD Diabetes eliminates relative cardioprotective effect of being premenopausal risk of recurrent MI in diabetic women is three times that of nondiabetic women Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women Kannel WB. Am Heart J. 1985;110:1100-1107. Abbott RD et al. JAMA. 1988;260:3456-3460.

Atherosclerosis in Diabetes ~80% of all diabetic mortality 75% from coronary atherosclerosis 25% from cerebral or peripheral vascular disease >75% of all hospitalizations for diabetic complications >50% of patients with newly diagnosed type 2 diabetes have CHD National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.

4S: Major CHD Event Reduction in a Patients With Diabetes Proportion without major CHD event 32% Diabetic, simvastatin - P=0.002 Diabetic, placebo 55% Nondiabetic, simvastatin - P=0.0001 Nondiabetic, placebo Yr since randomization Pyörälä K et al. Diabetes Care. 1997;20:614-620.

The Arterial Tree in Diabetes Conduit Artery Resistance Precapillary Capillaries Arterioles Arterioles Atherosclerosis Hypertension Retinopathy Neuropathy Nephropathy

UKPDS Blood Pressure Control blood pressure control reduced risk for Any diabetes-related endpoint 24% p=0.0046 diabetes-related deaths 32% p=0.019 stroke 44% p=0.013 microvascular disease 37% p=0.0092 heart failure 56% p=0.0043 retinopathy progression 34% p=0.0038 deterioration of vision 47% p=0.0036

Diabetes and CHD HOPE Study 9297 pts >55y.o. with DM or vascular disease + 1 CVD risk factor (~3578 DM ) Placebo or Ramipril 10 mg qd followed ~ 4 yrs Significant reductions in cardiovascular events (MI, stroke and CV death) Changes seen in both DM and non-DM groups

MICRO-HOPE No clinical proteinuria, CHF or diminished EF and not on ACE. 3577 patients with DM and either known CHD or one additional risk factor. Ramapril 10 mg/d or placebo. Study stopped at 4.5 yrs by DSMB

ACE Inhibition in DM

The Arterial Tree in Diabetes Conduit Artery Resistance Precapillary Capillaries Arterioles Arterioles Atherosclerosis Hypertension Retinopathy Neuropathy Nephropathy

Glucose Control Study Summary The intensive glucose control policy maintained a lower HbA1c by mean 0.9 % over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of: 12% for any diabetes related endpoint p=0.029 25% for microvascular endpoints p=0.0099 16% for myocardial infarction p=0.052 24% for cataract extraction p=0.046 21% for retinopathy at twelve years p=0.015 33% for albuminuria at twelve years p=0.000054

Effect of Improved Glycemic Control Quality of Life: Effect of Improved Glycemic Control P<.001 Improved P<.01 P<.01 Extended- release glipizide P<.05 Worsened Quality-of-Life Analog Rating Mental Health Cognitive Function General Perceived Health Symptom Distress Testa & Simonson, JAMA, 1998;280;1490-1496.

Glucose Control and Costs of Care A 6 year comparison between patients who improved glucose control (decline in HgbA1C >1%) or not has shown that improved glycemic control reduced annual health care costs for affected individuals Reductions due to fewer physican and emergency room visits Cost saving of $600-1000 annually.

Diabetes a preventable disease Several trials of diabetes prevention have been conducted for type 1 diabetes using vaccine strategies. None have yet been successful For Type 2 diabetes, multiple trials successfully demonstrated that both lifestyle changes and pharmacologic interventions can delay or prevent diabetes among individuals at high risk

Prevention of DM 2 F/U DM Incidence Study Control Diet Exercise Risk Reduction Study Control Diet Exercise Da Qing 6 Yr 68% 44% 31% DPS 4 Yr 23% 11% 58% DPP 3 Yr 29% 14%

Prevention of Diabetes with Lifestyle Modification

Effect of Metformin and Lifestyle Modification on New Onset Diabetes - Lifestyle changes work better as we age % Decline in Diabetes Incidence Subject Age

Okinawa 161 island archipelago, most live on main island, pop 1.3 m “Galapagos of the East” Lowest age-adjusted mortality (CHD, stroke, cancer) Longest disability-free life expectancy of 47 Japanese prefectures (states) Highest centenarian prevalence

Centenarians in the World (by prevalence) Willcox DC et al AGE 2006

Diabetes – A model for intervention in chronic disease As the population ages: Diabetes becomes more common Diabetes itself is more preventable by a healthy lifestyle Complications of diabetes while common can be prevented

Ushi Okushima 106 Years Young and Still Diggin’ Life Domo Arigato! Thank you !